tbuckley/cabot-search huggingface dataset:
CSIG-24. LINEAR GRADING COEFFICIENT REVEALS EMBRYONIC DEVELOPMENT GENE SIGNATURE AS TREATMENT-INDEPENDENT PROGNOSTIC FACTOR IN IDH-MUTANT ASTROCYTOMA
Authors: Santoesha Ghisai, Youri Hoogstrate, Mircea Tesileanu, Levi van Hijfte, Wies Vallentgoed, Iris de Heer, Matthias Preusser, Thierry Gorlia, Marc Sanson, Martin van den Bent, Pim French
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Since there is variation in prognosis within grade II/III and grade IV IDH-mutant astrocytomas, we sought to identify features that may aid further tumor grading. METHODS RNAseq was performed on IDH-mutant astrocytomas from the CATNON trial and overlaid with matching genome-wide methylation data. This dataset was extended by multi-omics data of IDH-mutant astrocytomas from the TCGA and GLASS-NL studies. We defined a linear grading coefficient (LGC) based on calibrated DNA methylation-based probability scores and performed differential gene expression (DGE) regression analysis on the LGC. Statistical analyses were intersected across the CATNON and TCGA cohorts ("discovery set") and validated on GLASS-NL. Single-nucleus RNA-sequencing (snRNAseq) data of high-grade IDH-mutant astrocytomas were utilized to explore the source of expression signals. Immunofluorescence was used to confirm findings on protein level. RESULTS DGE regression analysis revealed that higher-grade IDH-mutant tumors (high LGC) exhibited mRNA upregulation of key embryonic developmental transcription factors (HOX[A/C/D], NKX, PAX, and TBX). Although the vast majority of CpG sites in LGC high tumors were hypomethylated, homeobox genes were strongly hypermethylated in our discovery set. HOX gene clusters showed gene-ordered (differential) expression where e.g. HOXD10 &amp;gt;D9 &amp;gt;D8 &amp;gt;D4 &amp;gt;D1 and HOXA3 &amp;gt;A7 &amp;gt;A9 &amp;gt;A13 suggesting derepression of enhancer sequences up/downstream of the gene cluster. Our expression-based embryonic development signature was positively correlated with, but not restricted to, the G-CIMP-low subtype and homozygous CDKN2AB deletion. The signature was prognostic (log-rank test) on both the discovery (CATNON: p&amp;lt; 0.0005, TCGA: p&amp;lt; 0.0005) and validation set (GLASS-NL: p&amp;lt; 0.005). As our signature was developed on molecular data from primary resections, its prognostic value is treatment-independent. SnRNAseq on high-grade IDH-mutant astrocytomas indicated expression of embryonic development genes from tumor cells, not restricted to the stemness program. CONCLUSION Our study highlights upregulation of embryonic development genes as potential molecular mechanism associated with malignancy of IDH-mutant astrocytomas.
NIMG-58. PET IMAGING AS A RELIABLE INDICATOR FOR EVALUATING BEVACIZUMAB TREATMENT RESPONSE IN GBM
Authors: Keisuke Miyake, Kanda Takahiro, Kenta Suzuki, Takeshi Fujimori, Yasunori Toyota, Daisuke Ogawa, Tetsuhiro Hatakeyama, Masanobu Okauchi, Masahiko Kawanishi
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE PET scans are crucial for glioma diagnosis and treatment planning, but assessing the efficacy of Bevacizumab (Bev) treatment using MRI alone is challenging. Our study aimed to evaluate the effectiveness of Bev-based glioblastoma treatment using PET scans. METHODS We included ninety glioblastoma patients treated with Bev between July 2013 and May 2023. Patients were divided into three groups: the first group received Bev in addition to the Stupp regimen after biopsy or subtotal resection (first-dose group), the second group received Bev after biopsy followed by tumor resection (neoadjuvant group), and the third group received the Stupp regimen followed by TMZ + Bev at recurrence (recurrent group). PET scans (FDG, MET, FLT, and FMISO) were performed before and 4 weeks after starting Bev treatment. Tumor-to-normal ratio (TNR) was calculated for FDG, MET, and FLT, and tumor-to-blood ratio (TBR) was determined for FMISO. We used the Cox proportional hazards model to assess the percent change in TNR, TBR, and metabolic tumor volume (MTV) as prognostic factors. RESULTS The median PFS and OS (month) from Bev treatment were as follows: first-dose group (PFS: 8.87, OS: 12.53), neoadjuvant group (PFS: 16.53, OS: 22.13), and recurrent group (PFS: 4.0, OS: 8.0). In the first-line group, significant differences were found in the percent change in MTV for MET, FLT, and FMISO. In the recurrent group, significant differences were observed in the percent change in MTV for FDG and MET, as well as in FDG TNR and FMISO TBR. In the neoadjuvant group, significant differences were found in the percent change in MTV for MET and FLT. CONCLUSION Neoadjuvant Bev treatment led to prolonged PFS and OS in glioblastoma patients. Decreases in MET MTV change rate and FMISO TBR change rate were identified as potential indicators for assessing Bev treatment efficacy after recurrence.
MODL-43. SOX2 DOWNREGULATION OF PML PROMOTES HCMV GENE EXPRESSION AND GROWTH OF GLIOMA CELLS
Authors: Min-Hua Luo
Journal: Neuro-Oncology (2023)

Abstract The presence of human cytomegalovirus (HCMV) in glioblastoma (GBM) and improved outcomes of GBM patients receiving therapies targeting the virus have implicated HCMV in GBM progression. However, a unifying mechanism that accounts for the contribution of HCMV to the malignant phenotype of GBM remains incompletely defined. Here we have identified SOX2, a marker of glioma stem cells (GSCs), as a key determinant of HCMV gene expression in gliomas. Our studies demonstrated that SOX2 downregulated promyelocytic leukemia (PML) and Sp100 and consequently facilitated viral gene expression by decreasing the amount of PML nuclear bodies in HCMV-infected glioma cells. Conversely, the expression of PML antagonized the effects of SOX2 on HCMV gene expression. Furthermore, this regulation of SOX2 on HCMV infection was demonstrated in a neurosphere assay of GSCs and in a murine xenograft model utilizing xenografts from patient-derived glioma tissue. In both cases, SOX2 overexpression enhanced HCMV gene expression and facilitated the growth of neurospheres and xenografts implanted in immunodeficient mice. Lastly, the expression of SOX2 and HCMV immediate early 1 (IE1) protein could be correlated in tissues from glioma patients, and interestingly, elevated levels of SOX2 and IE1 were predictive of a worse clinical outcome. These studies argue that HCMV gene expression in gliomas is regulated by SOX2 through its regulation of PML expression and that targeting molecules in this SOX2-PML pathway could identify therapies for glioma treatment.
NIMG-80. SKULL BASE CHORDOMA: CORRELATION OF18F-FDG PET/CT FINDINGS WITH PATHOLOGICAL FEATURES AND CLINICAL COURSE
Authors: Yusuke Sakaguchi, Shota Tanaka, Hirokazu Takami, Masahiro Shin, Hirotaka Hasegawa, Hidemasa Takao, Shunsaku Takayanagi, Nobuhito Saito
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE This study aimed to evaluate 18F-fluorodeoxyglucose (FDG)-PET/CT findings, histopathological results, and clinical outcomes in patients with skull base chordoma. METHODS This retrospective study included patients who underwent first or repeat excision/biopsy for skull base chordoma at our institution between 2010 and 2019, with preoperative FDG-PET/CT. We assessed the SUVmean, SUVmax, lesion to white matter SUVmax/SUVmean ratio (L/N ratio), MIB-1 index, and occurrence of postoperative recurrence and metastasis. Statistical analysis was performed using Spearman's rank correlation coefficient and the Mann-Whitney U test. RESULTS Of the 17 participants, 52% were male, with a median age of 49 years (Interquartile Range: IQR 32-69). Among them, 41% were primary cases, and the median follow-up period was 51 months (IQR 32-77). The median SUVmax was 5.2 (IQR 3.9-6.2), SUVmean was 3.6 (IQR 3.1-5.1), L/N ratio was 1.5 (IQR 1.2-2.3), and MIB-1 index was 7.5% (IQR 2-10). Only SUVmax demonstrated a significant positive correlation with the MIB-1 index (ρ=0.556, p=0.021). Out of the 16 surgeries, 11 (69%) resulted in recurrence, while 4 of the total 17 cases (24%) showed metastasis. There were no significant differences in SUVmax, SUVmean, L/N ratio, and MIB-1 index between recurrence and non-recurrence groups. However, the MIB-1 index showed significant difference between metastasis and non-metastasis groups (p=0.0055). CONCLUSION In skull base chordoma, there was a significant correlation between the SUVmax on FDG-PET and the MIB-1 index. The MIB-1 index was significantly higher in the metastasis group. However, no significant correlation was found between SUVmax and distant metastasis, possibly due to the small sample size.
NIMG-74. COMPARING VOLUMETRIC GROWTH-RATE AND RANO CRITERIA IN DETERMINING THE RESPONSE OF MENINGIOMA TO BEVACIZUMAB THERAPY
Authors: Sara Borenstein, Alexandra Amiel, Tali Siegal, Omer Gal, Dror Limon, Ruth Eliahu, Shlomit Yust-Katz
Journal: Neuro-Oncology (2023)

Abstract Meningioma is the most prevalent primary tumor in the central nervous system (CNS). Although mostly benign, 15- 20% are aggressive and tend to recur and progress despite surgery and adjuvant radiation. Recent publications show that bevacizumab, a vascular endothelial growth factor inhibitor, effectively treats these refractory meningiomas. The standard method to monitor treatment’s effect on imaging is Response Assessment in Neuro-Oncology criteria (RANO). Recently, an alternative tool called 3D volumetric growth rate (3DVGR) has emerged. Our aim is to compare the effectiveness of conventional RANO criteria and the 3DVGR measure in evaluating the response to bevacizumab treatment in patients with refractory meningiomas. We will also assess their correlation with clinical outcomes over a period of up to 9 months. 68 MRI scans of 20 patients with aggressive meningiomas treated with bevacizumab were evaluated. For each tumor both RANO and 3DVGR were conducted in two subsequent head MRI studies acquired prior to the initiation of bevacizumab treatment and then in at least one exam within 6 months post-treatment. Measurements were obtained using PACS and BRAIN LAB software by two radiologists. A total of 43 lesions derived from 20 patients were included in the analysis. The mean age was 65.5; mean number of radiation treatments was 2.66; mean number of pre-surgical treatments was 2.7 and mean number of bevacizumab cycles was 22.7. All lesions showed a decrease or stabilization in growth rate compared to baseline. More specifically, 34 out of 43 lesions (79%) showed a negative growth rate value indicating decrease in tumor size. Comparison of treatment response using RANO criteria was not always in concordance with the 3DVGR measurement and showed inaccurate correlation with clinical outcome. 3DVGR measure seems to be more precise compared to RANO criteria. Furthermore, our results show great promise for treatment of refractory meningiomas with bevacizumab.
TMIC-84. A DEEP LEARNING-BASED METHOD FOR RAPID, PATIENT-SPECIFIC ASSAY OF MACROPHAGE INFILTRATION IN HIGH-GRADE GLIOMA USING LABEL-FREE STIMULATED RAMAN HISTOLOGY
Authors: Daniel Alber, Emily Lock, Karl Sangwon, Andrew Smith, Misha Movahed-Ezazi, Eric Oermann, Todd Hollon, Daniel Orringer
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND 5-Aminolevulinic acid (5-ALA), the most widely used fluorophore in image-guided glioma surgery, identifies tumor-associated macrophages (TAM) in high-grade glioma (HGG) tissue. Infiltrating macrophages, the predominant immune cells in glioma, are highly implicated in tumor progression, recurrence, and treatment response – particularly in immunotherapy. Using a unique, paired dataset of label-free stimulated Raman histology (SRH) and two-photon microscopy (TPEF) images sharing one-to-one spatial resolution, we developed a deep-learning approach to automatically quantify TAM infiltration from intraoperatively acquired SRH images. METHODS We compiled a dataset of 906 paired whole-slide SRH/TPEF images from 79 patients with HGG. We first trained a pix2pix generative adversarial network to convert raw, label-free SRH into synthetic TPEF with identifiable macrophages. Next, we trained a MaskR-CNN model to locate and segment TAMs. The pix2pix network was trained using 5,531 hand-picked 300-by-300-pixel fields-of-view (FOV) best exemplifying TAMs. We used a human-in-the-loop approach to train the segmentation network on 1,000 hand-labeled FOVs. RESULTS Macrophage segmentation from purely histologic data was near-identical to the fluorescence-based ground truth, with a mean dice score of 90.3%. Predicted TAM density was highly correlated with r=0.735. Subgroup analyses of TAM density in 346,836 non-overlapping FOVs revealed significantly lower TAM density in IDH-mutant (p&amp;lt; 0.01) and MGMT-hypermethylated (p=0.03) tumors. Our end-to-end algorithm uses fresh, unlabeled tissue specimens in the operating room and takes just three minutes to analyze whole-slide SRH images. CONCLUSION We demonstrate how deep neural networks can be used to rapidly and quantitatively evaluate macrophage infiltration in HGG in the operating room. Our software enables analysis of glioma patients’ tumor immune environment without immunohistochemistry or fluorescent labels, and may be leveraged to study the effects of immune-modulating therapies in the tumor microenvironment. Future work will focus on evaluating macrophage density and distribution as biomarkers for response to immunotherapies showing efficacy in glioma patients.
TMIC-32. IMPACT OF LOW-INTENSITY TRANSCRANIAL DIRECT-CURRENT STIMULATION (TDCS) IN GLIOBLASTOMA
Authors: Arabinda Das, Daniel G McDonald, Milad Yazdani, Cynthia A Welsh, Libby Kosnik Infinger, William A Vandergrift III, Abhay K Varma, Sunil J Patel, David Cachia, Alicia M Zukas, Scott M Lindhorst
Journal: Neuro-Oncology (2023)

Abstract The prognosis of glioblastoma (GBM) remains poor despite multiple attempts over the years to develop better treatment options for patients with this disease. Various challenges include an immunosuppressive tumor microenvironment, poor knowledge of the neuroimmune system, and the presence of the blood−brain barrier amongst others. To try and overcome some of these barriers, we used a low-intensity non-invasive transcranial direct current stimulation (tDCS) to suppress tumor growth and enhance the immune response in preclinical glioblastoma cell culture and animal model. This study reports for the first time that treatment of GBM and rGBM (recurrent GBM) cells with tDCS (50 mV/mm for 30 min), can modulate the expression of human leukocyte antigen (HLA) class II molecules such as HLA-DR alpha, HLA-DR complex, invariant chain (Ii), and HLA-DM (an important catalyst of the class II-peptide loading). Furthermore, we demonstrated in vivo that tDCS [350 μA (1 x 30 min/day) treatment 7 times (within 14 Days) showed a significant (~30%) decrease in GBM tumor growth in an orthotopic allograft GL261 GBM mouse model (at Day 41). Following tDCS treatment, our results demonstrated the downregulation of Ki-67 in treated tumors. Also, we observed the upregulation of CD38 (M1 macrophages) and CD8+ T cells in treated cells in vivo. Based on our preliminary data from in vitro and in vivo studies, we believe that this study suggests that induction of immune components of the HLA class II pathway by tDCS may be a promising therapeutic strategy for the treatment of human GBM.
CNSC-22. CANCER NEUROSCIENCE IN THE OR: ELECTROPHYSIOLOGIC INSIGHTS AT THE TIME OF BRAIN TUMOR RESECTION
Authors: Thomas Nelson, Brian Coughlin, Daniel Cahill, Gavin Dunn, Brian V Nahed, G Rees Cosgrove, Jimmy Yang, Hannah Farnsworth, R Mark Richardson, Sydney Cash, Humsa Venkatesh, Angelique Paulk
Journal: Neuro-Oncology (2023)

Abstract Pioneering works by Venkatesh and Venkataramani demonstrated that formation of functional neural-glial synapses fosters development and growth of glial neoplasms. Resultant peritumoral neural hyperexcitability associates with tumor progression, though limited in vivo human data have been evaluated to date. We sought to enrich our understanding of these mechanisms by obtaining thin film intraoperative micro-electrocorticography (µECoG) recordings from patients undergoing primary brain tumor resection. METHODS: Intraoperative µECoG data for 8 patients with low- (LGG) and high-grade glioma (HGG, WHO grades 3 and 4) of various tumor histology were included. Analyses excluded any operative behavioral or cognitive tasks and evaluated data prior to stimulation for language or motor mapping. Following low pass (&amp;lt; 200 Hz) and notch filtering at 60, 120, and 180 Hz for ambient electrical noise, bandpower was calculated using multitaper spectral analysis for low frequency (LF, &amp;lt; 1 Hz), delta (1-4 Hz), beta (12-30 Hz), gamma (30-80 Hz), and high gamma (80-200 Hz) bands. RESULTS: Compared to isocitrate dehydrogenase (IDH) wild-type tumors, those with IDH-mutation (n = 3; two WHO grade 3, one grade 4) demonstrated the highest proportion of power within the LF band (92.2% vs 71.4%) with relatively lower proportional beta (3.6% vs 18.3%) and gamma (2.2% vs 8.7%) bandpower. The same pattern was seen in HGG (n = 5) vs LGG (n = 3) tumors with higher LF (84.5% vs 70.3%) and lower beta (10.3% vs 16.8%) and gamma (3.5% vs 10.8%) bandpower, perhaps driven by three HGGs with IDH mutation. Absolute bandpower was highest at all bands in a patient with left frontal glioblastoma. CONCLUSIONS: Interesting patterns are emerging that corroborate differential high and low frequency neural activity among patients with primary brain tumors. Disparities in LF and beta/gamma bands may represent therapeutic targets or a non-invasive biomarker of disease activity but require further, ongoing data collection and analyses.
PATH-51. GENETIC CHARACTERIZATION AND MUTATIONAL PROFILING OF FORAMEN MAGNUM MENINGIOMAS: A MULTI-INSTITUTIONAL STUDY
Authors: Lingyang Hua, Shingo Fujio, Majd Alkhatib, Sylvia Herold, Ilker Eyuepoglu, Victoria Clark, Hiroaki Wakimoto, Ganesh M Shankar, Daniel Cahill, Priscilla Brastianos, Gabriele Schackert, Tareq Juratli
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE Foramen magnum (FM) meningiomas pose significant surgical challenges and have high morbidity and mortality rates. This study aims to investigate the distribution of clinically actionable mutations in FM meningiomas and identify clinical characteristics associated with specific mutational profiles. METHODS We conducted targeted next-generation sequencing of 62 FM meningiomas from three international institutions, covering all relevant meningioma genes (AKT1, KLF4, NF2, POLR2A, PIK3CA, SMO, and TRAF7). Additionally, we retrospectively collected and evaluated patient and tumor characteristics, including age, sex, radiological features, and tumor location. RESULTS Our cohort consisted of 46 female and 16 male patients. Clinically significant driver mutations were detected in 58 patients (93.5%). The most commonly observed alteration was TRAF7 mutations (n=26, 41.9%), followed by AKT1(E17K) mutations (n=19, 30.6%). Both mutations were significantly associated with an anterolateral tumor location relative to the brainstem (p=0.0078). Tumors harboring these mutations predominantly (89.3%) displayed meningiothelial histology. NF2 mutations were present in 11 cases (17.7%) and were associated with posterior tumor location, in contrast to tumors with TRAF7 and AKT1(E17K) mutations. Other common mutations in FM meningiomas included POLR2A mutations (n=8, 12.9%), KLF4 mutations (n=7, 11.6%), and PIK3CA mutations (n=3, 4.8%). These mutations exclusively occurred in female patients and showed no significant correlation with specific tumor locations. Eight tumors exhibited intratumoral calcification which was significantly more frequent in NF2-mutant compared with AKT1-mutant FM meningiomas (p=0.047). CONCLUSIONS Our findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.
TMIC-56. DECIPHERING THE INTRICATE GLIOBLASTOMA TUMOR MICROENVIRONMENT AND EGFRVIII TRANSCRIPT DISTRIBUTION THROUGH SINGLE-CELL SPATIAL PROFILING
Authors: Simon Gregory, Vaibhav Jain, Emily Hocke, Karen Abramson, Elizabeth Thomas, Diane Satterfield, Kyle Walsh, Michael Brown, Roger McLendon, David Ashley
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Profiling the tumor microenvironment (TME) in glioblastoma (GBM) poses challenges due to its complex and heterogeneous nature. Analyzing diverse cell populations, deciphering dynamic cell-cell interactions, and overcoming spatial-temporal variations present significant challenges to characterizing the GBM TME. These challenges can, in part, be overcome using in situ sequencing (ISS) approaches that offer the advantage of directly analyzing gene expression within intact tissue, providing spatial and molecular context for understanding complex biological processes and tumor heterogeneity. Method/ RESULTS Here, we report a ‘first in world’ application of 10xGenomics Xenium ISS platform to profiling RNA expression profiles within GBM tissue, including primary and recurrent tumors, to establish single cell-level profiling of the TME. Our panel of canonical and custom GBM genes allowed us to establish profiles of high-resolution cell neighborhoods, intratumoral cell-types and cell-states, and the distribution of infiltrating tumor cells throughout the tissue. Exploiting the chemistry that underlies the Xenium platform, we also developed a novel ISS isoform expression assay that semi-quantitatively profiles a mutated variant of the epidermal growth factor receptor (EGFR). Data show that EGFRvIII, which has been shown to promote tumor growth, invasion, and resistance to therapies, is preferentially expressed within tumor-subsets within the GBM. Our EGFRvIII assay not only has the potential to act as a high sensitivity method of tumor diagnosis but its distribution will allow for correlation of this tumorigenic marker with activated pathways across the tissue. CONCLUSION ISS is a valuable tool for profiling the complex TME in GBM, enabling analysis of intratumoral cell types, cell states, and EGFRvIII distribution. Our study demonstrates its pioneering application, offering insights into the molecular landscape and potential for novel diagnostic signatures and improved treatment strategies for this aggressive cancer.